Early Detection Poses Challenge

Glaucoma may strike individuals of any age, but it is most prevalent in people over the age of 60. For Black Americans, the rate of prevalence ticks up much earlier, at about 40 years of age, and people with diabetes or a family history of the condition are also more susceptible. Because glaucoma is asymptomatic in initial stages, early diagnosis is challenging.

The disease occurs when the optic nerve and the retinal ganglion cells — which relay visual inputs to the central nervous system — are damaged; elevated pressure in the eye, or intraocular pressure, is the main culprit. When fluid accumulates in the eye, such as from overproduction or improper drainage, it increases intraocular pressure and also the risk of developing glaucoma. Symptoms appear slowly, with changes in peripheral vision occurring before forward-facing vision becomes compromised.

Comprehensive eye exams can catch glaucoma in earlier stages, as these screenings involve optic nerve examination, intraocular pressure measurement, visual field testing and risk factor assessment. Patients must be proactive about regular screenings because once vision is lost, it cannot be repaired or restored. Available therapies can stop glaucoma’s progression and generally focus on alleviating intraocular pressure, but early diagnosis remains key.

Building on Existing Diagnostic Tools

Advances in diagnostic tools can give clinicians more and better information for treating glaucoma. Optical coherence tomography (OCT), for instance, uses light-wave imaging to help assess the optic nerve’s structural integrity. More recently, OCT angiography (OCTA) has been adopted to consider the optic nerve’s support system, such as blood supply. Functional imaging may be the next wave, as it should enable clinicians to identify cells under oxidative stress and take corrective action before irreversible damage is done.

Understanding a patient’s visual field is critical to identifying ocular diseases, and virtual reality goggles are emerging as a user-friendly, portable device. Doheny Eye Institute, dedicated to vision science, is investigating VR to enhance existing field vision testing and foresees future assessments that could bypass patient response. With its predictive powers, AI should also have a diagnostic role; AI may identify factors that clinicians could overlook when determining the risk of disease, progression, and aggressiveness so that patients can be treated early and accordingly.

Treatment Options Keep Evolving

Patients have various treatment options for glaucoma and generally take one of three paths: medication, laser or surgery. In the past five years, two new medications have surfaced, each with a novel mechanism of action that is additive to clinicians’ arsenals. The rho kinase inhibitor works to lower intraocular pressure, while a nitric oxide medication has dual action, reducing pressure and improving blood flow and oxygen to the optic nerve head. Research organizations like Doheny Eye Institute are also investing in the drug delivery arena, seeking ways to reduce patient error in medication administration and improve outcomes.

Laser treatment is nothing new in treating glaucoma, but techniques and instruments are constantly being refined. Laser trabeculoplasty has gained more acceptance, and as a minimally invasive procedure, it provides relief by reducing intraocular pressure. A more recent introduction, micropulse transscleral laser therapy also relieves intraocular pressure but by delivering energy in short pulses, which appears to minimize collateral tissue damage.

Should patients be beyond medication or non-invasive procedures, incisional surgery remains an option to improve natural drainage of the eye or insert an implant to create an accessory drainage pathway. Advances in surgical procedures, implants and devices continue to be sought after in research circles.

The Future Lies in Neuroprotection

Glaucoma research is a dynamic field, and an emergent focus is neuroprotection, where treatment extends beyond decreasing intraocular pressure to intervention in the chemical pathways that lead to the death of retinal ganglion cells. This exciting area considers protective effects, such as a drug therapy that could prevent cells from dying. It also explores how cells could be resuscitated, or what interventions could return damaged cells to their full functionality. Ultimately, this field of study is working toward neuro regeneration, where neural pathways may be fully restored so that lost vision may be regained.

With continued advances in glaucoma-related research and development across the board — from diagnostics and devices to pharmaceuticals and drug delivery to laser and surgical procedures — the future for patients is looking brighter. Maintaining momentum will be key for researchers to achieve the ultimate goal and find a cure for existing and future glaucoma patients.

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This May, the 2024 Annual Meeting was held in Seattle, and after taking some time to absorb the whirlwind of activity and insights, three elements stand out:

1. ARVO is back!

The pandemic changed the face of many conferences and meetings, and ARVO was no exception. This year, the annual meeting returned to pre-pandemic levels of attendance and participation, and the energy and enthusiasm were palpable. The number of abstract presentations and scientific research presentations rebounded, and I was very proud of the large showing by my colleagues and fellow vision scientists from Doheny Eye Institute and UCLA; Doheny contributed 67 papers and posters among a total of 155 from UCLA.

In addition to the many new learning opportunities, there were a number of opportunities for forging collaborations and networking. Growing connections within the scientific community is essential to expanding our thinking and considering new methods of achieving outcomes to benefit all.

2. Tech innovations are driving progress.

Artificial intelligence has been a hot topic in almost every industry in recent years. In vision science, we’re seeing many developments in AI that have the potential to enhance assessments and diagnoses, as well as to quantify disease features precisely, something previously thought not possible.

Additionally, incredible gains are being made in genetic science and gene-based therapies. The recent groundbreaking FDA approval for a gene-editing approach to addressing sickle cell anemia, which can affect the eye, opens the door to other patient trials and new gene-based therapeutics.

In parallel with these advances in genetic and molecular therapies, significant progress is happening in high-resolution diagnostic technologies. For example, my colleagues at Doheny and UCLA demonstrated, for the first time, visualization of metabolic processes in individual retinal cells in the living eye.

Exciting innovation in the tech space inspires the ARVO 2025 Annual Meeting, which has the theme of “i3: Imagining Innovation and Intelligence in Vision Science.”

3. We need to communicate.

The closing keynote speech focused on a topic that some don’t readily associate with the scientific community: communication. The vision science community is producing incredible work and results, and while we are adept at sharing technical information with vision science colleagues, we cannot necessarily take the same approach with other audiences.

Communication needs to be tailored to reach various stakeholder groups, from the general public to policymakers to government and philanthropic organizations that hold the keys to funding. Advocacy is one of the pillars of ARVO’s five-year strategic plan, developed in 2023. We can only grow advocacy for our cause if we can clearly communicate its impact and importance.

Start planning for 2025.

ARVO 2025 Annual Meeting will be held in Salt Lake City, Utah, May 4-8, and as the newly appointed president of ARVO, I am already deep into the planning stages. If the 2024 meeting is anything to go by, our 2025 gathering will offer compelling content and unparalleled opportunities for collaboration and engagement. I invite all members of the vision science community to join me!

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Not all cases of AMD are created equal

AMD takes on one of two forms: wet AMD or dry AMD. Wet AMD, or choroidal neovascularization, is less prevalent but also treatable. It is characterized by abnormal blood vessel growth into the retina, and that intrusion and leakage of blood into the retina disrupt the photoreceptors, which causes a disruption to vision. Patients may notice that once straight lines appear wavy, or they could have a blank spot in their central vision. The onset of symptoms is relatively rapid, but treatments can effectively promote a regression of blood vessels and help restore vision. Only about 10% of patients with AMD have this treatable form.

Dry AMD, on the other hand, occurs in more than 80% of patients and no time-tested treatments exist. This slow progressing disease involves the death of the retinal pigment epithelium (RPE), cells that support the health of the light-sensing photoreceptors by serving as a conduit for nutrients and oxygen from the outer retinal blood supply. Importantly, the RPE cells have no regenerative potential, so once this critical support system is lost, photoreceptors are prone to damage and loss.

Typically, patients learn they have the condition at regular eye exams, where an ophthalmologist may identify drusen (tiny bits of debris in the back of the eye), or when they begin experiencing impaired vision, at which point they are often in an advanced stage, or geographic atrophy (GA). The FDA has only recently approved two therapies intended for dry AMD, but their efficacy for a broad patient population has not yet been determined.

Identifying pathways is key

Both new therapies for dry AMD target the complement pathway. Part of the immune system and present in all tissues, the complement pathway surveys for invading pathogens and removes them, which is a good thing. It can go into overdrive or behave erratically, however, which can result in the destruction of good tissue. New treatments are formulated to keep the complement pathway in check and inhibit it from destroying cells in the eye, as this destruction is a mechanism for dry AMD.

While the new therapies are promising, they target just one of potentially many mechanisms for the condition. Researchers have successfully used genetics to identify specific pathways that appear to increase the risks of developing dry AMD, with dozens of different genes found to be potential culprits. In just the past decade or so, at least six different pathways that could contribute to the onset of dry AMD have also been uncovered.

One relatively recent development includes the discovery that the mitochondria, the cell’s center for generating energy, is compromised in the RPE cells early in the disease, which could indicate a potential pathological event contributing to dry AMD onset. Cell culture models are replicating the findings, and further investigation points to a specific population that carries the complement factor H risk allele and appears more susceptible to mitochondrial disruption.

In addition to exploring the mitochondrial factor, researchers are working to understand other risk alleles and the biology behind them. By understanding the biological processes that go awry early on in dry AMD, investigators should be able to develop more targeted therapies. Further, coupling scientific research with the frontline experience of ophthalmologists can help to identify and understand which pathway is impacting a particular patient so that treatment can be tailored to achieve the best possible outcome. Even with wet AMD, the available treatments are not effective in all patients, which suggests that the remedies are overlooking a key mechanism in some individuals.

Research progresses amidst challenges

The scientific community has persisted in advancing dry AMD research, although this particular disease presents some challenges. Genetics is only one piece of the puzzle. Environmental factors also play a role for individuals, as a history of smoking or poor diet, for instance, can elevate the danger of developing dry AMD. And because AMD is an age-onset disease, it may be near impossible to pinpoint what, in a 50- or 60-year lifetime, set an individual on their path to disease.

Animal models representative of the human condition are highly valuable in medical research, but AMD researchers are hard-pressed to find a close approximation due to the unique features of the human eye and the contribution of aging. To maintain momentum in their field, AMD researchers are turning to different types of cultured cells. Induced pluripotent stem cells (iPSCs) are a somewhat recent innovation and have shown considerable potential.

Mature cells are taken from an adult, and those cells have their development reversed to the point at which they become like a fetal cell. At that juncture, they can be differentiated into any cell in the body, including RPE cells, and be studied in a dish to learn AMD’s underlying pathophysiology and identify potential treatments. Future progress with iPSCs include using patient-specific cells to identify the optimal treatment for each patient, possibly opening the door to personalized medicine — the Holy Grail of medicine by some estimations. 

For AMD researchers, one of the most valuable sources for IPSCs are eye banks, where people have donated their eyes to medical research. Scientists have made major discoveries from accessing and comparing eyes of those individuals with AMD to those without the disease. In addition to studying the tissues itself, researchers can generate critical iPSCs from the donations, furthering the impact of the donation and moving investigators closer to new, effective therapies.

Pressing ahead with intention

Recent FDA approval of dry AMD therapies is encouraging, but the work is not done. Considering the genetic and environmental variations in the millions of patients currently and potentially coping with the disease, more than a one-size-fits-all approach will be needed to transform lives for the better. Researchers must continue to ask critical questions about cellular changes associated with aging, factors that influence pathology, cellular responses to disease, and the potential to protect against pathologic changes. As such mysteries are unraveled, the scientific community will move closer to discovering groundbreaking therapies for this widespread, life-altering condition.

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AI builds on earlier computer vision efforts

Earlier efforts of applying computer vision techniques to analyze images involved creating a hard-coded algorithm containing rules that machines should follow in their search. While this method has worked well in many cases, where it fails is in cases that are outliers or are presented in a manner inconsistent with what models have been told to seek. To capture those types of instances, it would be necessary to revise the algorithm by writing new sets of rules as scenarios arise — an arduous and time-consuming process.

With AI-based approaches, researchers can feed thousands upon thousands of images to a system that will review and sort all the data it comes across, allowing it to detect patterns and to generalize. It is not foolproof, as encountering a not-yet-seen image will require some intervention to confirm whether that image should be added to a database, but this adjustment is relatively simple and allows AI to refine its learning quickly and serve as a more valuable, timely resource with compelling potential for patient care.

Medical AI algorithm offers clarity

Already, one of the first FDA-cleared medical AI algorithms is making a life-changing impact for patients around the world. A collaboration between Doheny Eye Institute and Eyenuk, leveraging NIH-sponsored grants, has resulted in a new screening system to detect diabetic retinopathy, a condition that can result in vision loss and blindness in people with diabetes. Screening is vitally important because 90% of diabetic blindness is preventable with timely detection and treatment.

For the AI screening tool, experts in image reading participated in algorithm development and training by furnishing annotated images of cases ranging from mild, non-proliferative retinopathy to the most severe stage of proliferative retinopathy. With the data input, the algorithm was trained to identify whether patients exhibited retinopathy that warranted a visit to an ophthalmologist to avoid future vision loss.

In the case of diabetic retinopathy, early stages of the condition may go unnoticed, or if the symptoms appear manageable, patients may postpone a visit to their physician. An AI screening tool offers the possibility of garnering greater compliance with recommendations for regular assessment. Capturing an image of the eye at a primary care physician’s office or even on a smartphone at home and sharing it with AI in the cloud for an immediate diagnosis could promote early detection and, hopefully, prevent blindness.

Similar work is being conducted in the area of age-related macular degeneration (AMD). Algorithms are being developed to detect features in patients with AMD to help physicians identify those who may be at high risk of progression to more advanced stages. The information can assist doctors in closer monitoring of at-risk individuals and in developing a treatment course.

Adding another tool to the toolbox

The advent of AI has ushered in countless conversations about the technology’s impact — good and bad — and the medical field has certainly not been immune to the debates. For one, AI is not perfect, and it can and will make mistakes. It’s necessary to consider the output of large language models that have generated hearsay or misinformation, and human experts must approach any output with a healthy dose of skepticism and be unafraid to challenge results.

Additionally, the application of any new technology, like AI, may result in unintended consequences. Should medical AI models become widely available, there is a risk that those without proper credentials may try to use them to make decisions, or to question decisions, which are best left to licensed medical professionals. AI models can provide actionable knowledge, but they will lack the broader context of a patient’s circumstances, values and conditions that their physicians should understand and consider in a holistic treatment plan.

If harnessed with care, AI has the ability to provide medical professionals with another tool to elevate patient care. Each case is unique and deserves a personalized approach, and AI may help doctors optimize their selection of treatment options. Physicians could leverage information furnished by AI, such as from clinical trials, and compare it alongside an individual’s characteristics to arrive at a care approach with the best chance for success.

AI is poised to be instrumental in the decision-making process for physicians, but ultimately, it cannot replace the human element. Medicine is much more than determining a diagnosis, and tough discussions and difficult decisions require empathy that only another human being can provide. With AI as an assistive tool, it opens the door for physicians to access more information and context to aid in making treatment recommendations and ultimately help improve their patients’ outcomes.

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